Oh MC, Sayegh ET, Safaee M, et al.
Prognosis by tumor location for pediatric spinal cord ependymomas.
J Neurosurg Pediatr. 2013; 11(3):282-8 [PubMed]

OBJECT: Ependymoma is a common CNS tumor in children, with spinal cord ependymomas making up 13.1% of all ependymomas in this age group. The clinical features that affect prognosis in pediatric spinal cord ependymomas are not well understood. A comprehensive literature review was performed to determine whether a tumor location along the spinal cord is prognostically significant in children undergoing surgery for spinal cord ependymomas.
METHODS: A PubMed search was performed to identify all papers that contained data on patients with spinal cord ependymomas. Only pediatric patients (age < 18 years) who underwent resection with a clearly reported tumor location were included in the analysis. Myxopapillary tumors were excluded from study. Tumor location was subdivided into 6 regions: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus medullaris. Kaplan-Meier survival and Cox regression analyses were performed to determine the effects of tumor location on progression-free survival (PFS) and overall survival (OS).
RESULTS: Fifty-eight patients who underwent resection of spinal cord ependymomas were identified. Ependymomas were located all along the spinal cord but occurred with the highest frequency in the cervical region (29.3%). Progression-free survival was significantly better in patients with tumors arising in the upper portion of the spinal cord (p = 0.031), which remained significant in the multivariate Cox regression analysis (p < 0.05). Moreover, OS was significantly better in patients with upper spinal cord ependymomas than in those harboring ependymomas in the lower spinal cord (p = 0.048).
CONCLUSIONS: Although more common in adults, spinal ependymomas can occur anywhere along the spinal cord in the pediatric population; however, tumors occurring in the lower half of the spinal cord carry a worse prognosis with shorter PFS and OS. By comparison, ependymomas in the upper spinal cord recur later and less frequently, with little or no mortality in this patient group.

Modena P, Buttarelli FR, Miceli R, et al.
Predictors of outcome in an AIEOP series of childhood ependymomas: a multifactorial analysis.
Neuro Oncol. 2012; 14(11):1346-56 [PubMed] Article available free on PMC after 01/11/2013

Several molecular biomarkers have been suggested as predictors of outcome for pediatric ependymomas but deserve further validation in independent case series. We analyzed intracranial ependymomas belonging to a series of 60 patients prospectively treated according to the protocol sponsored by the Italian Association of Pediatric Hematology-Oncology. We used a tissue microarray to analyze nucleolin (NCL), cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and epidermal growth factor receptor (EGFR) by immunohistochemistry and by 1q gain by fluorescent in situ hybridization. The mRNA expression levels of EGFR, human telomerase reverse-transcriptase (HTERT), and Prominin 1 (PROM 1)/CD133 were evaluated by quantitative real-time PCR from cases with fresh-frozen tumor material available. Univariate and multivariate analyses of updated clinical data confirmed the prognostic significance of surgery (P < .01) and tumor grading (P < .05) for both relapse-free survival (RFS) and overall survival (OS). Among biomolecular markers, HTERT mRNA expression emerged with the strongest association with OS at multivariate analysis (hazard ratio [HR] = 9.9; P = .011); the 5-year OS was 84% versus 48% in the subgroups with HTERT median value <6 versus ≥ 6, respectively (P = .005). Five-year RFS was 46% versus 20% in the subgroups with low versus high NCL protein expression, respectively (P = .004), while multivariate Cox analyses gave suggestively high HRs for high versus low NCL (HR = 1.9; P = .090). The other genes tested were not significant at multivariate analyses, and genetic alterations of CDKN2A, TP53, EGFR, and HTERT loci were rare. The PROM1/CD133 cancer stem cell marker was strongly expressed at both RNA and protein levels in a substantial fraction of cases and was suggestively associated with a more indolent form of the disease. We conclude that NCL and HTERT represent the strongest prognostic biomarkers of RFS and OS, respectively, in our ependymoma case series.

Gururangan S, Fangusaro J, Young Poussaint T, et al.
Lack of efficacy of bevacizumab + irinotecan in cases of pediatric recurrent ependymoma--a Pediatric Brain Tumor Consortium study.
Neuro Oncol. 2012; 14(11):1404-12 [PubMed] Article available free on PMC after 01/11/2013

A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in cases of pediatric recurrent ependymoma (EPN) to estimate sustained objective response rate and progression-free survival (PFS). Eligible patients received 2 doses of single-agent BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ + CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion-weighted and T1 dynamic contrast enhanced permeability imaging and tumor immunohistochemistry for vascular endothelial growth factor (VEGF)-A and -B, hypoxia inducible factor-2α, VEGF receptor (R)-2, and carbonic anhydrase (CA)-9. Thirteen evaluable patients received a median of 3 courses (range, 2-12) of BVZ + CPT-11. No sustained response was observed in any patient. Median time to progression in 10 patients was 2.2 months (range, 1.9-6.3). Two patients had stable disease for 10 months and 12 months, respectively. Six-month PFS was 25.7% (SE = 11.1%). Grades I-III toxicities related to BVZ treatment included fatigue in 4 patients, systemic hypertension in 2, epistaxis in 1, headache in 1, and avascular necrosis of bone in 1. Although there was a decrease in the mean diffusion ratio following 2 doses of BVZ, it did not correlate with PFS. BVZ + CPT-11 was well tolerated but had minimal efficacy in cases of recurrent EPN.

Benesch M, Frappaz D, Massimino M
Spinal cord ependymomas in children and adolescents.
Childs Nerv Syst. 2012; 28(12):2017-28 [PubMed]

BACKGROUND: Spinal cord ependymomas are very rare among children and adolescents. Due to their rarity, our current knowledge of these tumors is based on case reports and few retrospective case series.
METHODS: The present review summarizes the currently available literature on childhood spinal cord ependymomas.
RESULTS: Although overall survival rates are favorable, relapse incidence is high, particularly in myxopapillary ependymomas. Since long-term follow-up data are provided in a limited number of studies only, the true relapse incidence is unknown. Maximal safe radical surgery is the backbone of treatment for children with spinal cord ependymomas, but the impact of adjuvant treatment on progression and survival is still unclear. Presently, the decision to initiate non-surgical treatment depends primarily on the WHO grade of the tumor and the extent of resection. In terms of the known side effects, early radiotherapy should be avoided in children with WHO grade II spinal cord ependymomas irrespective of the extent of resection but is indicated in anaplastic spinal cord ependymomas both after complete and incomplete resection. The high relapse incidence in myxopapillary ependymomas argue for the use of early radiotherapy, but its definitive impact on progression has to be proven in larger series. Close surveillance is important due to the high recurrence rate in all patients with spinal cord ependymomas.
CONCLUSION: Prospective collection of both clinical and molecular data from a greater number of patients with spinal cord ependymomas within an international collaboration is the prerequisite to establish standardized management guidelines for these rare CNS tumors.

Garvin JH, Selch MT, Holmes E, et al.
Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Group protocol 9942: a report from the Children's Oncology Group.
Pediatr Blood Cancer. 2012; 59(7):1183-9 [PubMed]

PURPOSE: Standard therapy for childhood intracranial ependymoma is maximal tumor resection followed by involved-field irradiation. Although not used routinely, chemotherapy has produced objective responses in ependymoma, both at recurrence and in infants. Because the presence of residual tumor following surgery is consistently associated with inferior outcome, the potential impact of pre-irradiation chemotherapy was investigated.
METHODS: Between 1995 and 1999, the Children's Cancer Group undertook a Phase II trial of pre-irradiation chemotherapy in children 3-21 years of age with intracranial ependymoma and radiological evidence of post-operative residual tumor.
RESULTS: Of 84 patients, 41 had residual tumor, and were given four cycles of cisplatin-based chemotherapy prior to irradiation. Of 35 patients fully evaluable for response to chemotherapy, 14 (40%) demonstrated complete response, 6 (17%) partial response, 10 (29%) minor response or stable disease, and 5 (14%) demonstrated progressive tumor growth. For the entire group, 5-year overall survival (OS) and event-free survival (EFS) was 71 ± 6%, and 57 ± 6%, respectively. The pre-irradiation chemotherapy group demonstrated EFS comparable to that of patients with no residual tumor who received irradiation alone (55 ± 8% vs. 58 ± 9%, P = 0.45). Any benefit of chemotherapy was restricted to patients with greater than 90% tumor resection.
CONCLUSIONS: Children with near total resection of ependymoma may benefit from pre-irradiation chemotherapy. Patients with subtotal resection have inferior outcome despite responses to chemotherapy, and should be considered for second-look surgery prior to irradiation. Pediatr Blood Cancer 2012; 59: 1183-1189. © 2012 Wiley Periodicals, Inc.

Jia Y, Beltran C, Indelicato DJ, et al.
Proton therapy dose distribution comparison between Monte Carlo and a treatment planning system for pediatric patients with ependymoma.
Med Phys. 2012; 39(8):4742-7 [PubMed]

PURPOSE: Compare dose distributions for pediatric patients with ependymoma calculated using a Monte Carlo (MC) system and a clinical treatment planning system (TPS).
METHODS: Plans from ten pediatric patients with ependymoma treated using double scatter proton therapy were exported from the TPS and calculated in our MC system. A field by field comparison of the distal edge (80% and 20%), distal fall off (80% to 20%), field width (50% to 50%), and penumbra (80% to 20%) were examined. In addition, the target dose for the full plan was compared.
RESULTS: For the 32 fields from the 10 patients, the average differences of distal edge at 80% and 20% on central axis between MC and TPS are -1.9 ± 1.7 mm (p < 0.001) and -0.6 ± 2.3 mm (p = 0.13), respectively. Excluding the fields that ranged out in bone or an air cavity, the 80% difference was -0.9 ± 1.7 mm (p = 0.09). The negative value indicates that MC was on average shallower than TPS. The average difference of the 63 field widths of the 10 patients is -0.7 ± 1.0 mm (p < 0.001), negative indicating on average the MC had a smaller field width. On average, the difference in the penumbra was 2.3 ± 2.1 mm (p < 0.001). The average of the mean clinical target volume dose differences is -1.8% (p = 0.001), negative indicating a lower dose for MC.
CONCLUSIONS: Overall, the MC system and TPS gave similar results for field width, the 20% distal edge, and the target coverage. For the 80% distal edge and lateral penumbra, there was slight disagreement; however, the difference was less than 2 mm and occurred primarily in highly heterogeneous areas. These differences highlight that the TPS dose calculation cannot be automatically regarded as correct.

Amirian ES, Armstrong TS, Aldape KD, et al.
Predictors of survival among pediatric and adult ependymoma cases: a study using Surveillance, Epidemiology, and End Results data from 1973 to 2007.
Neuroepidemiology. 2012; 39(2):116-24 [PubMed] Article available free on PMC after 28/07/2013

BACKGROUND: Despite previous research, prognostic factors for ependymoma remain relatively controversial. The purpose of our study was to examine demographic, clinical, and tumor attributes as potential predictors of survival using Surveillance, Epidemiology, and End Results (SEER) program data (1973-2007).
METHODS: All ependymoma (ICD-O-3 code 9391) and anaplastic ependymoma cases (ICD-O-3 code 9392) with complete data (n = 2,369 and n = 319, respectively) were included from SEER. Predictive Cox regression models were built separately among pediatric and adult cases. Recursive partitioning was used to corroborate results from regression models.
RESULTS: Among pediatric cases, tumor characteristics with a significantly increased mortality risk were anaplastic histology (vs. low grade, HR: 1.51, 95% CI: 1.04-2.19) and infratentorial tumor location (vs. spinal cord, HR: 3.86, 95% CI: 1.17-12.77). Among adults, supratentorial tumors were associated with higher mortality hazard (vs. spinal cord tumors) than infratentorial tumors (HR: 4.83, 95% CI: 3.49-6.68 and HR: 2.41, 95% CI: 1.79-3.25, respectively). Complete surgical resection of the tumor conferred the most protection among pediatric and adult patients.
CONCLUSION: Our results indicate that treatment type and tumor characteristics are important prognostic factors in patients with ependymoma. However, there may be key differences between pediatric and adult cases regarding how these factors influence survival.

Agbahiwe HC, Wharam M, Batra S, et al.
Management of pediatric myxopapillary ependymoma: the role of adjuvant radiation.
Int J Radiat Oncol Biol Phys. 2013; 85(2):421-7 [PubMed]

INTRODUCTION: Myxopapillary ependymoma (MPE) is a rare tumor in children. The primary treatment is gross total resection (GTR), with no clearly defined role for adjuvant radiation therapy (RT). Published reports, however, suggest that children with MPE present with a more aggressive disease course. The goal of this study was to assess the role of adjuvant RT in pediatric patients with MPE.
METHODS: Sixteen patients with MPE seen at Johns Hopkins Hospital (JHH) between November 1984 and December 2010 were retrospectively reviewed. Fifteen of the patients were evaluable with a mean age of 16.8 years (range, 12-21 years). Kaplan-Meier curves and descriptive statistics were used for analysis.
RESULTS: All patients received surgery as the initial treatment modality. Surgery consisted of either a GTR or a subtotal resection (STR). The median dose of adjuvant RT was 50.4 Gy (range, 45-54 Gy). All patients receiving RT were treated at the involved site. After a median follow-up of 7.2 years (range, 0.75-26.4 years), all patients were alive with stable disease. Local control at 5 and 10 years was 62.5% and 30%, respectively, for surgery alone versus 100% at both time points for surgery and adjuvant RT. Fifty percent of the patients receiving surgery alone had local failure. All patients receiving STR alone had local failure compared to 33% of patients receiving GTR alone. One patient in the surgery and adjuvant RT group developed a distant site of recurrence 1 year from diagnosis. No late toxicity was reported at last follow-up, and neurologic symptoms either improved or remained stable following surgery with or without RT.
CONCLUSIONS: Adjuvant RT improved local control compared to surgery alone and should be considered after surgical resection in pediatric patients with MPE.

Godfraind C, Kaczmarska JM, Kocak M, et al.
Distinct disease-risk groups in pediatric supratentorial and posterior fossa ependymomas.
Acta Neuropathol. 2012; 124(2):247-57 [PubMed] Article available free on PMC after 01/08/2013

No reliable classification is in clinical use for the therapeutic stratification of children with ependymoma, such that disease risk might be identified and patients treated to ensure a combination of maximal cure rates and minimal adverse therapeutic effects. This study has examined associations between clinicopathologic and cytogenetic variables and outcome in a trial cohort of children with ependymoma, with the aim of defining a practical scheme for stratifying this heterogeneous tumor. Intracranial ependymomas (n = 146) from children treated on the RT1 trial at St. Jude Children's Research Hospital were evaluated for the status of multiple pathological features. Interphase FISH (iFISH) defined the status of loci on chromosomes 1q (EXO1), 6q (LATS1) and 9, including 9p21 (CDKN2A). Data relating to these clinicopathological and cytogenetic variables were compared with survival data in order to model disease risk groups. Extent of surgical resection was a significant determinant of outcome in both supratentorial and infratentorial compartments. Tumor cell density and mitotic count were associated with outcome among children with posterior fossa ependymomas (n = 119). Among pathologic features, only brain invasion was associated with outcome in children with supratentorial ependymomas (n = 27). For posterior fossa tumors, gain of 1q was independently associated with outcome and in combination with clinicopathological variables defined both a two-tier and three-tier system of disease risk. Among children developing posterior fossa ependymomas treated with maximal surgical resection and conformal radiotherapy, key clinicopathological variables and chromosome 1q status can be used to define tiers of disease risk. In contrast, risk factors for pediatric supratentorial tumors are limited to sub-total resection and brain invasion.

Gimi B, Cederberg K, Derinkuyu B, et al.
Utility of apparent diffusion coefficient ratios in distinguishing common pediatric cerebellar tumors.
Acad Radiol. 2012; 19(7):794-800 [PubMed]

RATIONALE AND OBJECTIVES: The aim of this study was to identify clinically useful tumor/normal brain apparent diffusion coefficient (ADC) ratios for distinguishing common pediatric cerebellar tumors.
MATERIALS AND METHODS: Review of medical records revealed 79 patients with cerebellar tumors who underwent preoperative magnetic resonance imaging, including diffusion-weighted imaging sequences, and surgery. There were 31 pilocytic astrocytomas, 27 medulloblastomas, 14 ependymomas, and seven atypical teratoid/rhabdoid tumors. ADC values were measured by placing regions of interest on the solid tumor and normal brain parenchyma by two reviewers. Tumor/normal brain ADC ratios were calculated.
RESULTS: Mean ADC values of the pilocytic astrocytomas were greater than those of ependymomas, whose mean ADC values were greater than those of medulloblastomas and atypical teratoid/rhabdoid tumors. Using a tumor/normal brain ADC ratio threshold of 1.70 to distinguish pilocytic astrocytomas from ependymomas, sensitivity of 92% and specificity of 79% were achieved. A tumor/normal brain ADC ratio threshold of 1.20 enabled the sorting of ependymomas from medulloblastomas with sensitivity of 93% and specificity of 88%.
CONCLUSIONS: Tumor/normal brain ADC ratios allow the distinguishing of common pediatric cerebellar tumors.

Mohindra S, Rane S, Gupta SK
Symptomatic apoplexy in intramedullary ependymoma: a report of a pediatric patient.
Pediatr Neurosurg. 2011; 47(5):369-71 [PubMed]

Spinal intramedullary ependymomas often harbor clinically asymptomatic intratumoral bleeds. Such tumors presenting with apoplectic events have not been described in the literature. The authors report on a 2-year-old female who presented with sudden loss of sensorimotor functions below the thoracic spine as a consequence of hemorrhage within an intramedullary ependymoma. The clinical, radiological, and surgical findings are described. Gross total resection provided near-normal spinal functions in the present case.

Kilday JP, Mitra B, Domerg C, et al.
Copy number gain of 1q25 predicts poor progression-free survival for pediatric intracranial ependymomas and enables patient risk stratification: a prospective European clinical trial cohort analysis on behalf of the Children's Cancer Leukaemia Group (CCLG), Societe Francaise d'Oncologie Pediatrique (SFOP), and International Society for Pediatric Oncology (SIOP).
Clin Cancer Res. 2012; 18(7):2001-11 [PubMed]

PURPOSE: The high incidence of recurrence and unpredictable clinical outcome for pediatric ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. We therefore evaluated 1q25 gain across three age- and treatment-defined European clinical trial cohorts of pediatric intracranial ependymoma.
EXPERIMENTAL DESIGN: Frequency of 1q gain was assessed across 48 ependymomas (42 primary, 6 recurrent) using Affymetrix 500K single-nucleotide polymorphism arrays. Gain of 1q25 was then evaluated by interphase FISH across 189 tumors treated on the Children's Cancer Leukaemia Group/International Society for Pediatric Oncology (SIOP) CNS9204 (n = 60) and BBSFOP (n = 65) adjuvant chemotherapy trials, or with primary postoperative radiotherapy (SIOP CNS9904/RT, n = 64). Results were correlated with clinical, histologic, and survival data.
RESULTS: Gain of 1q was the most frequent imbalance in primary (7/42, 17%) and recurrent ependymomas (2/6, 33%). Gain of 1q25 was an independent predictor of tumor progression across the pooled trial cohort [HR = 2.55; 95% confidence interval (CI): 1.56-4.16; P = 0.0002] and both CNS9204 (HR = 4.03; 95% CI: 1.88-8.63) and BBSFOP (HR = 3.10; 95% CI: 1.22-7.86) groups. The only clinical variable associated with adverse outcome was incomplete tumor resection. Integrating tumor resectability with 1q25 status enabled stratification of cases into disease progression risk groups for all three trial cohorts.
CONCLUSIONS: This is the first study to validate a prognostic genomic marker for childhood ependymoma across independent trial groups. 1q25 gain predicts disease progression and can contribute to patient risk stratification. We advocate the prospective evaluation of 1q25 gain as an adverse marker in future international clinical trials.

Khatua S, Sadighi ZS, Pearlman ML, et al.
Brain tumors in children--current therapies and newer directions.
Indian J Pediatr. 2012; 79(7):922-7 [PubMed]

Brain tumors are the second most common malignancy and the major cause of cancer related mortality in children. Though significant advances in neuroimaging, neurosurgery, radiation therapy and chemotherapy have evolved over the years, overall survival rate remains less than 75%. Malignant gliomas, high risk medulloblastoma with recurrence and infant brain tumors continue to be a major cause of therapeutic frustration. Even today diffuse pontine gliomas are universally fatal. Though tumors like low grade glioma have an overall excellent survival, recurrences and progression in eloquent areas pose therapeutic challenges. As research continues to unravel the biology including key molecules and signaling pathways responsible for the oncogenesis of different childhood brain tumors, novel targeted therapies are profiled. Identification of major targets like the Epidermal Growth factor Receptor (EGFR), Platelet Derived Growth Factor Receptor (PDGFR), Vascular Endothelial Growth factor (VEGF) and key signaling pathways like the MAPK and PI3K/Akt/mTOR has enabled us over the recent years to better understand tumor behavior and design tailored therapy. These efforts have improved overall survival of children with brain tumors. This review article discusses the current status of common brain tumors in children and the newer therapeutic approaches.

De Smet HJ, Catsman-Berrevoets C, Aarsen F, et al.
Auditory-perceptual speech analysis in children with cerebellar tumours: a long-term follow-up study.
Eur J Paediatr Neurol. 2012; 16(5):434-42 [PubMed]

Mutism and Subsequent Dysarthria (MSD) and the Posterior Fossa Syndrome (PFS) have become well-recognized clinical entities which may develop after resection of cerebellar tumours. However, speech characteristics following a period of mutism have not been documented in much detail. This study carried out a perceptual speech analysis in 24 children and adolescents (of whom 12 became mute in the immediate postoperative phase) 1-12.2 years after cerebellar tumour resection. The most prominent speech deficits in this study were distorted vowels, slow rate, voice tremor, and monopitch. Factors influencing long-term speech disturbances are presence or absence of postoperative PFS, the localisation of the surgical lesion and the type of adjuvant treatment. Long-term speech deficits may be present up to 12 years post-surgery. The speech deficits found in children and adolescents with cerebellar lesions following cerebellar tumour surgery do not necessarily resemble adult speech characteristics of ataxic dysarthria.

Bouffet E, Hawkins CE, Ballourah W, et al.
Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation.
Int J Radiat Oncol Biol Phys. 2012; 83(5):1541-8 [PubMed]

PURPOSE: The outcome of recurrent ependymoma in children is dismal. Reirradiation has been proposed as an effective modality for ependymoma at relapse. However, the toxicity and outcome benefits of this approach have not been well established.
METHODS AND MATERIALS: We conducted a retrospective population-based study of all patients with recurrent ependymoma treated between 1986 and 2010 in our institution. Demographic, treatment, and outcome data were analyzed for the entire cohort.
RESULTS: Of 113 patients with intracranial ependymoma, 47 patients relapsed. At the time of relapse, 29 patients were treated with surgical resection and/or chemotherapy, and 18 patients received full-dose (≥ 54 Gy focal and/or craniospinal) reirradiation with or without surgery at recurrence. Reirradiation was tolerated well with no severe acute complications noticed. Three-year overall survival was 7% ± 6% and 81% ± 12% for nonreirradiated and reirradiated patients, respectively (p < 0.0001). Time to second progression after reirradiation was significantly longer than time to first progression. This surprising phenomenon was associated with improved progression-free survival for tumors with evidence of DNA damage (n = 15; p = 0.002). At a mean follow-up of 3.73 years, only 2/18 patients had endocrine dysfunction, and 1 patient required special education support. However, a decline in intellectual function from pre- to postreirradiation assessment was observed.
CONCLUSIONS: Reirradiation is an effective treatment that may change the natural history of recurrent ependymoma in children. However, this change may be associated with increased neurocognitive toxicity. Additional follow-up is needed to determine the risk of late recurrence, secondary radiation-induced tumors, and long-term functional outcome of these patients.

Rajappa P, Krass J, Riina HA, et al.
Super-selective basilar artery infusion of bevacizumab and cetuximab for multiply recurrent pediatric ependymoma.
Interv Neuroradiol. 2011; 17(4):459-65 [PubMed] Article available free on PMC after 01/08/2013

Ependymoma is a central nervous system tumor associated with a poor prognosis due to limited efficacy of current medical treatment modalities, often resulting in multiple surgical re-resections with each tumor recurrence. As traditional chemotherapeutic regimens have proved unsuccessful in long-term control of subtotally resected ependymoma, other agents targeting the tumor microenvironement including the angiogenic factors supplying neovascularization have recently been used. Anti-angiogenic agents such as bevacizumab are routinely used in adult patients with recurrent glioma. Selective intra-arterial cerebral infusion (SIACI) of biological agents within tumor-supplying cerebral vasculature has recently been re-examined as a means to avoid the systemic side-effects associated with intravenous use of bevacizumab. This technical paper describes the first reported use of SIACI for delivery of two targeted biologic agents, bevacizumab and cetuximab in a pediatric patient utilizing the basilar artery to selectively administer the drugs to the tumor microenvironment. We believe this method for therapeutic delivery will both broaden treatment options and better refine treatment methodology as the multi-modality treatment approach often required to treat patients with pediatric ependymomas and other intracranial malignancies evolves.

van Vuurden DG, Hulleman E, Meijer OL, et al.
PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation.
Oncotarget. 2011; 2(12):984-96 [PubMed] Article available free on PMC after 01/08/2013

Poly ADP-ribose polymerase (PARP) is a protein involved in single strand break repair. Recently, PARP inhibitors have shown considerable promise in the treatment of several cancers, both in monotherapy and in combination with cytotoxic agents. Synthetic lethal action of PARP inhibitors has been observed in tumors with mutations in double strand break repair pathways. In addition, PARP inhibition potentially enhances sensitivity of tumor cells to DNA damaging agents, including radiotherapy. Aim of this study is to determine the radiosensitizing properties of the PARP inhibitor Olaparib in childhood medulloblastoma, ependymoma and high grade glioma (HGG). Increased PARP1 expression was observed in medulloblastoma, ependymoma and HGG, as compared to non-neoplastic brain tissue. Pediatric high grade glioma, medulloblastoma and ependymoma gene expression profiling revealed that high PARP1 expression is associated with poor prognosis. Cell growth inhibition assays with Olaparib resulted in differential sensitivity, with IC50 values ranging from 1.4 to 8.4 µM, irrespective of tumor type and PARP1 protein expression. Sensitization to radiation was observed in medulloblastoma, ependymoma and HGG cell lines with subcytotoxic concentrations of Olaparib, which coincided with persistence of double strand breaks. Combining PARP inhibitors with radiotherapy in clinical studies in childhood high grade brain tumors may improve therapeutic outcome.

Rogers HA, Kilday JP, Mayne C, et al.
Supratentorial and spinal pediatric ependymomas display a hypermethylated phenotype which includes the loss of tumor suppressor genes involved in the control of cell growth and death.
Acta Neuropathol. 2012; 123(5):711-25 [PubMed] Article available free on PMC after 01/08/2013

Epigenetic alterations, including methylation, have been shown to be an important mechanism of gene silencing in cancer. Ependymoma has been well characterized at the DNA copy number and mRNA expression levels. However little is known about DNA methylation changes. To gain a more global view of the methylation profile of ependymoma we conducted an array-based analysis. Our data demonstrated tumors to segregate according to their location in the CNS, which was associated with a difference in the global level of methylation. Supratentorial and spinal tumors displayed significantly more hypermethylated genes than posterior fossa tumors, similar to the 'CpG island methylator phenotype' (CIMP) identified in glioma and colon carcinoma. This hypermethylated profile was associated with an increase in expression of genes encoding for proteins involved in methylating DNA, suggesting an underlying mechanism. An integrated analysis of methylation and mRNA expression array data allowed us to identify methylation-induced expression changes. Most notably genes involved in the control of cell growth and death and the immune system were identified, including members of the JNK pathway and PPARG. In conclusion, we have generated a global view of the methylation profile of ependymoma. The data suggests epigenetic silencing of tumor suppressor genes is an important mechanism in the pathogenesis of supratentorial and spinal, but not posterior fossa ependymomas. Hypermethylation correlated with a decrease in expression of a number of tumor suppressor genes and pathways that could be playing an important role in tumor pathogenesis.

Sung KW, Lim do H, Lee SH, et al.
Tandem high-dose chemotherapy and autologous stem cell transplantation for anaplastic ependymoma in children younger than 3 years of age.
J Neurooncol. 2012; 107(2):335-42 [PubMed]

The present study evaluates the feasibility and effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) in very young children with anaplastic ependymoma. We aimed both to improve survival and to avoid unacceptable late adverse effects of radiation therapy (RT) by avoiding or deferring RT until 3 years of age. Five consecutive patients younger than 3 years of age with anaplastic ependymoma were enrolled from April 2006 to November 2008. Tandem HDCT/autoSCT was given following six cycles of induction chemotherapy. RT was either not given or deferred until 3 years of age if the patient was in complete response after tandem HDCT/autoSCT. Median age at diagnosis was 16 (range 12-28) months. Four patients had significant residual tumor (>1.5 cm(2)) after initial surgery, and three had leptomeningeal seeding. Toxicities during induction chemotherapy and tandem HDCT/autoSCT were manageable. No tumor progressed during induction chemotherapy and tandem HDCT/autoSCT, and RT was thus avoided or deferred until 3 years of age in all patients. All patients are alive at median follow-up of 45 (range 31-62) months from diagnosis, although tumor progressed in one patient. No significant endocrine dysfunction occurred except for hypothyroidism in one patient. Cognitive function was also acceptable in all patients but one who had significant neurologic injury during surgery. Our results indicate that treatment with tandem HDCT/autoSCT is feasible in very young children with anaplastic ependymoma and may improve the survival of patients with acceptable long-term toxicity.

Pinho RS, Andreoni S, Silva NS, et al.
Pediatric central nervous system tumors: a single-center experience from 1989 to 2009.
J Pediatr Hematol Oncol. 2011; 33(8):605-9 [PubMed]

The objective of this study was to determine the epidemiology of primary tumors of the central nervous system (CNS) in pediatric patients from a Brazilian oncology institute. We retrospectively analyzed 741 charts (415 males and 326 females) of patients under 21 years of age who were diagnosed with a CNS tumor. The analysis included patients from 1989 to 2009 and was performed using the World Health Organization criteria. We evaluated the distribution of age, sex, topography, clinical symptoms, symptom intervals, and classification of the tumors. Patients with clinical/radiologic diagnoses were included. Seven hundred forty-one patients with tumors in the CNS were reviewed, and 83% of the patients presented a histologic diagnosis. Males (56%) were more prevalent than females. In children under the age of 1 year, the supratentorial compartment was the predominant region involved (62.0%). Astrocytoma was the most frequent tumor type (37.0%), followed by medulloblastoma (13.6%), craniopharyngioma (10.5%), and ependymoma (6.8%). Headaches were the most common symptom, and the symptom intervals varied from 1 to 5010 days. Approximately 4% of the patients had associated genetic syndromes. Although it was not a population study and selection bias may have occurred, this study supplies important epidemiologic data from an emerging country in which population studies are rare.

Eshraghi H, Andronikou S, Fisher-Jeffes N, et al.
Anaplastic clear cell ependymoma of the conus medullaris and cauda equina in a 3-year-old child.
J Pediatr Hematol Oncol. 2012; 34(4):316-7 [PubMed]

Only a minority of ependymomas present in the spinal cord. We report on a child with recurrence of a rare anaplastic clear cell type of ependymoma. This was initially misdiagnosed as a World Health Organization grade I myxopapillary ependymoma because this type of ependymoma occurs more commonly and the magnetic resonance imaging features and location at the conus medullaris were considered characteristic.

Forbes JA, Reig AS, Smith JG, et al.
Findings on preoperative brain MRI predict histopathology in children with cerebellar neoplasms.
Pediatr Neurosurg. 2011; 47(1):51-9 [PubMed] Article available free on PMC after 01/08/2013

BACKGROUND/AIMS: The majority of pediatric patients with cerebellar neoplasms harbor pilocytic astrocytomas (PAs), medulloblastomas, or ependymomas. Knowledge of a preoperative likelihood of histopathology in this group of patients has the potential to influence many aspects of care. Previous studies have demonstrated hyperintensity on diffusion-weighted imaging to correlate with medulloblastomas. Recently, measurement of T(2)-weighted signal intensity (T2SI) was shown to be useful in identification of low-grade cerebellar neoplasms. The goal of this study was to assess whether objective findings on these MRI sequences reliably correlated with the underlying histopathology.
METHODS: We reviewed the radiologic findings of 50 pediatric patients who underwent resection of a cerebellar neoplasm since 2003 at our institution. Region of interest placement was used to calculate the relative diffusion-weighted signal intensity (rDWSI) and relative T2SI (rT2SI) of each neoplasm.
RESULTS: Tukey's multiple comparison test demonstrated medulloblastomas to have significantly higher rDWSIs than PAs/ependymomas, and PAs to have significantly higher rT2SIs than medulloblastomas/ependymomas. A simple method consisting of sequential measurement of rDWSI and rT2SI to predict histopathology was then constructed. Using this method, 39 of 50 (78%) tumors were accurately predicted.
CONCLUSION: Measurement of rDWSI and rT2SI using standard MRI of the brain can be used to predict histopathology with favorable accuracy in pediatric patients with cerebellar tumors.

Grill J, Bergthold G, Ferreira C
Pediatric ependymomas: will molecular biology change patient management?
Curr Opin Oncol. 2011; 23(6):638-42 [PubMed]

PURPOSE OF REVIEW: Ependymomas remain a therapeutic challenge in pediatric neuro-oncology. These tumors are chemoresistant and rather radioresistant and until recently little was known about their biology.
RECENT FINDINGS: Histopathological grading of ependymomas according to the WHO classification is neither reproducible, nor correlated with outcome, especially in young children. Characterization of molecular abnormalities in ependymomas offers now a better understanding of their initiation and progression; different biological subtypes of tumors have been described and would need further validation. The identification of new prognostic biomarkers, such as tenascin-C overexpression or chromosome 1q gain, will considerably help patient stratification in future trials. Finally, the recent discovery of specific pathways involved in ependymomas oncogenesis, such as Notch-1or EPHB2 offers new perspectives for the development of targeted therapies.
SUMMARY: A comprehensive biological work-out including CGHarray and immunohistochemistry for specific biomarkers should now be recommended for the current management of pediatric ependymoma, especially in young children if radiotherapy has to be omitted in the first line of treatment.

Phi JH, Wang KC, Park SH, et al.
Pediatric infratentorial ependymoma: prognostic significance of anaplastic histology.
J Neurooncol. 2012; 106(3):619-26 [PubMed]

Pediatric infratentorial ependymomas are difficult to cure. Despite the availability of advanced therapeutic modalities for brain tumors, total surgical resection remains the most important prognostic factor. Recently, histological grade emerged as an independent prognostic factor for intracranial ependymoma. We retrospectively reviewed the treatment outcome of 33 pediatric patients with infratentorial ependymoma. Progression-free survival (PFS) and overall survival (OS) rates were calculated and relevant prognostic factors were analyzed. Fourteen patients (42%) were under the age of 3 at diagnosis. Gross total resection was achieved in 16 patients (49%). Anaplastic histology was found in 13 patients (39%). Adjuvant therapies were delayed until progression in 12 patients (36%). Actuarial PFS rates were 64% in the first year and 29% in the fifth year. Actuarial OS rates were 91% in the first year and 71% in the fifth year. On univariate analysis, brainstem invasion (P = 0.047), anaplastic histology (P = 0.004), higher mitotic count (P = 0.001), and higher Ki-67 index (P = 0.004) were significantly related to a shorter PFS. Gross total resection (P = 0.029) and a greater age at diagnosis (P = 0.033) were significantly related to a longer PFS. On multivariate analysis, anaplastic histology alone was significantly related to a shorter PFS (P = 0.023). Gross total resection (P = 0.039) was significantly related to a longer overall survival (OS) on multivariate analysis. Anaplastic histology and gross total resection were the most important clinical factors affecting PFS and OS, respectively. Anaplastic histology, mitotic count, and Ki-67 index can be used as universal and easily available prognostic parameters in infratentorial ependymomas.

Pejavar S, Polley MY, Rosenberg-Wohl S, et al.
Pediatric intracranial ependymoma: the roles of surgery, radiation and chemotherapy.
J Neurooncol. 2012; 106(2):367-75 [PubMed]

Management of pediatric intracranial ependymomas poses a major challenge, and optimal treatment remains controversial. We sought to investigate the roles of surgery, radiation, and chemotherapy in a historical cohort. Thirty-nine children, age 21 or younger, with non-metastatic intracranial ependymomas were treated from 1972 to 2008. Median age was 8 years (range 0.2-19.1). Twenty-one patients (54%) underwent GTRs, and 18 (45%) underwent STRs. Twenty-six patients (67%) received upfront adjuvant RT (67%), and 14 (44%) received adjuvant chemotherapy. Twenty-four patients had disease recurrence and 12 died. Only one patient recurred after 5 years. Median PFS was 2.7 years and median OS was 20 years. Fifteen year PFS and OS were 30 and 67%. Adjuvant RT was associated with improved PFS (P = 0.045), and remained significant after adjusting for EOR (P = 0.04). Greater EOR trended towards prolonged survival, but did not reach statistical significance (P = 0.156). Of the patients that underwent GTR, the median PFS was 38 months for those treated with adjuvant RT versus 30 months for those that were not treated with RT. Of the patients that had STR, the median PFS for those treated with RT was 26.3 months versus 6.9 months for those were not treated with RT. In conclusion, for localized intracranial pediatric ependymomas, adjuvant RT is associated with improved PFS, even after adjusting for EOR. Our findings suggest the benefit of RT even in the presence of GTR. Future prospective studies with larger sample number are needed to validate our findings.

Ma L, Xiao SY, Liu XS, et al.
Intracranial extraaxial ependymoma in children: a rare case report and review of the literature.
Neurol Sci. 2012; 33(1):151-4 [PubMed]

Intracranial extraaxial ependymomas (IEAEs) are extremely rare. We present a pediatric patient with IEAE misdiagnosed as a meningioma preoperatively, successfully treated surgically with a favorite outcome. The literature about IEAEs was briefly reviewed. Thereafter we discuss the clinical characteristics of the disease.

Koshy M, Rich S, Merchant TE, et al.
Post-operative radiation improves survival in children younger than 3 years with intracranial ependymoma.
J Neurooncol. 2011; 105(3):583-90 [PubMed]

Concerns regarding long-term toxicities have led to the avoidance of post-operative radiation (PORT) in young children with intracranial ependymoma. We investigated the association between post-operative radiation therapy and overall survival (OS) in children younger than 3 years and compared their survival to other age groups. The study sample from the SEER database included 804 patients with intracranial ependymoma, grades 2-3, and diagnosed between 1988 and 2005. OS was estimated using the Kaplan-Meier method, and hazard ratios (HR) and 95% confidence limits (CL) were calculated based on multivariable Cox proportional hazards models. A total of 804 patients were selected and PORT was administered to 35% of patients younger than 3 years. With a median follow-up of 3 years (range 0.1-18 years), the 3 year OS was 61% for children younger than 3 years, 83% for those ages 3-20 years, and 69% for patients older than 20 years (P < 0.001). In multivariable analysis, OS was significantly improved for patients receiving PORT (HR 0.8, 95% CL 0.6-0.9), and gross total resection (HR 0.6, 95% CL 0.5-0.8). Among children younger than 3 years, the 3 year OS was significantly greater among those who received PORT compared to those who did not (81% vs. 56%, respectively, P = 0.005). The majority of children younger than 3 years with intracranial ependymoma did not receive PORT. Children younger than 3 years who did not receive PORT had a relatively poor outcome, while those who received radiation therapy had a survival similar to older patients.

Ellison DW, Kocak M, Figarella-Branger D, et al.
Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts.
J Negat Results Biomed. 2011; 10:7 [PubMed] Article available free on PMC after 01/08/2013

BACKGROUND: Histopathological grading of ependymoma has been controversial with respect to its reproducibility and clinical significance. In a 3-phase study, we reviewed the pathology of 229 intracranial ependymomas from European trial cohorts of infants (2 trials - SFOP/CNS9204) and older children (2 trials - AIEOP/CNS9904) to assess both diagnostic concordance among five neuropathologists and the prognostic utility of histopathological variables, particularly tumor grading.
RESULTS: In phase 1, using WHO criteria and without first discussing any issue related to grading ependymomas, pathologists assessed and independently graded ependymomas from 3 of 4 trial cohorts. Diagnosis of grade II ependymoma was less frequent than grade III, a difference that increased when one cohort (CNS9204) was reassessed in phase 2, during which the pathologists discussed ependymoma grading, jointly reviewed all CNS9204 tumors, and defined a novel grading system based on the WHO classification. In phase 3, repeat independent review of two cohorts (SFOP/CNS9904) using the novel system was associated with a substantial increase in concordance on grading. Extent of tumor resection was significantly associated with progression-free survival (PFS) in SFOP and AIEOP, but not in CNS9204 and CNS9904. Strength of consensus on grade was significantly associated with PFS in only one trial cohort (AIEOP). Consensus on the scoring of individual histopathological features (necrosis, angiogenesis, cell density, and mitotic activity) correlated with PFS in AIEOP, but in no other trial.
CONCLUSIONS: We conclude that concordance on grading ependymomas can be improved by using a more prescribed scheme based on the WHO classification. Unfortunately, this appears to have utility in limited clinical settings.

Venkatramani R, Dhall G, Patel M, et al.
Supratentorial ependymoma in children: to observe or to treat following gross total resection?
Pediatr Blood Cancer. 2012; 58(3):380-3 [PubMed]

BACKGROUND: The standard treatment for ependymoma is surgical resection followed by postoperative irradiation to the local site. The role of radiation therapy in completely resected supratentorial ependymoma has been questioned over the past two decades.
PROCEDURE: Retrospective review of the medical records of all consecutively diagnosed supratentorial ependymoma patients at Children's Hospital Los Angeles between January 1999 and December 2009.
RESULTS: Ten patients (three females) were included. The median age at presentation was 5.6 years (range 1.8-15.6 years). Reviewed histology was anaplastic ependymoma in seven patients and cellular ependymoma in three patients. Gross total resection was achieved in six patients; five were observed and one received chemotherapy. In the four patients who underwent subtotal resection, one was observed, two received local irradiation and one received irradiation and chemotherapy. The median length of follow up was 43 (range 22-81) months. Four relapses were observed; two patients who underwent initial gross total resection. All patients who underwent gross total resection were alive at the time of preparation of this article. The 5-year progression-free and overall survival rates were 53 ± 19% and 86 ± 13% respectively.
CONCLUSIONS: Radiation therapy was avoided in five patients following gross total resection, four of whom had anaplastic histology. In some children with completely resected supratentorial ependymoma, surgery alone may be an acceptable treatment option.

Gephart MG, Taft BP, Giese AK, et al.
Perioperative posterior reversible encephalopathy syndrome in 2 pediatric neurosurgery patients with brainstem ependymoma.
J Neurosurg Pediatr. 2011; 7(3):235-7 [PubMed]

Posterior reversible encephalopathy syndrome (PRES) has been described in pediatric neurooncology patients, although it has not been documented perioperatively in pediatric neurosurgery patients not actively receiving chemotherapy. Recently at the authors' facility, 2 cases of PRES were diagnosed perioperatively in children with brainstem ependymoma. Both patients had presented with hypertension, altered mental status, and seizures and demonstrated MR imaging features consistent with PRES. The patients were treated with antiseizure and antihypertension medications, leading to improvement in both clinical symptoms and neuroimaging findings. These cases are the first to document PRES in perioperative pediatric neurosurgery patients not actively receiving chemotherapy. Both patients had ependymoma involving the brainstem, which may have led to intra- and perioperative hemodynamic instability (including hypertension) and predisposed them to this syndrome. An awareness of PRES in similar scenarios will aid in the prevention, diagnosis, and treatment of pediatric neurosurgery patients with this syndrome.